Optimization of a series of 2,4-diaminopyridines as neuropeptide Y Y1 receptor antagonists with reduced hERG activity

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 15, 2009, Pages 4325-4329

  Kameda, Minoru ^a   Kobayashi, Kensuke ^a   Ito, Hirokatsu ^a   Miyazoe, Hiroshi ^a   Tsujino, Toshiaki ^a   Nakama, Chisato ^a   Kawamoto, Hiroshi ^a   Ando, Makoto ^a   Ito, Sayaka ^a   Suzuki, Tomoki ^a   Kanno, Tetsuya ^a   Tanaka, Takeshi ^a   Tahara, Yoshio ^a   Tani, Takeshi ^a   Tanaka, Sachiko ^a   Tokita, Shigeru ^a   Sato, Nagaaki ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

2,4 Diaminopyridine derivatives; Antagonist; Anti obesity; Food intake inhibition; NPY; Y1 Receptor

Indexed keywords

2,4 DIAMINOPYRIDINE; ANOREXIGENIC AGENT; NEUROPEPTIDE Y1 RECEPTOR; PYRIDINE DERIVATIVE; TRANSCRIPTION FACTOR ERG; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; DRUG MECHANISM; DRUG STRUCTURE; DRUG SYNTHESIS; MOUSE; NONHUMAN;

4-AMINOPYRIDINE; ANIMALS; CELL LINE; CHEMISTRY, PHARMACEUTICAL; CHO CELLS; CRICETINAE; CRICETULUS; DRUG DESIGN; ETHER-A-GO-GO POTASSIUM CHANNELS; HUMANS; HYDROGEN-ION CONCENTRATION; INHIBITORY CONCENTRATION 50; MODELS, CHEMICAL; RECEPTORS, NEUROPEPTIDE Y; RECOMBINANT PROTEINS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 67649987378     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.05.069     Document Type: Article

References (29)

1. Tatemoto K., Carlquist M., and Mutt V. Nature 296 (1982) 659
2. Odonohue T.L., Chronwall B.M., Pruss R.M., Mezey E., Kiss J.Z., Eiden L.E., Massari V.J., Tessel R.E., Pickel V.M., Dimaggio D.A., Hotchkiss A.J., Crowley W.R., and ZukowskaGrojec Z. Peptides 6 (1985) 755
3. Tatemoto K., Mann M.J., and Shimizu M. Proc. Natl. Acad. Sci. U.S.A. 89 (1992) 1174
4. Stanley B.G., and Leibowitz S.F. Proc. Natl. Acad. Sci. U.S.A. 82 (1985) 3940
5. Stanley B.G., Magdalin W., Seirafi A., Nguyen M.M., and Leibowitz S.F. Peptides 13 (1992) 581
6. Zarjevski N., Cusin I., Vettor R., RohnerJeanrenaud F., and Jeanrenaud B. Endocrinology 133 (1993) 1753
7. Erickson J.C., Hollopeter G., and Palmiter R.D. Science 274 (1996) 1704
8. Blomqvist A.G., and Herzog H. Trends Neurosci. 20 (1997) 294
9. Eva C., Serra M., Mele P., Panzica G., and Oberto A. Front. Neuroendocrinol. 27 (2006) 308
10. For recent reviews:. Ishihara A., Moriya M., MacNeil D.J., Fukami T., and Kanatani A. Expert Opin. Ther. Pat. 16 (2006) 1701
11. MacNeil D.J. Curr. Top. Med. Chem. 7 (2007) 1721
12. Kanatani A., Hata M., Mashiko S., Ishihara A., Okamoto O., Haga Y., Ohe T., Kanno T., Murai N., Ishii Y., Fukuroda T., Fukami T., and Ihara M. Mol. Pharmacol. 59 (2001) 501
13. Fukami, T.; Mase, T.; Tsuchiya, Y.; Kanatani, A.; Fukuroda, T. PCT Int. Appl. WO 9734873.
14. Sato N., Shibata T., Jitsuoka M., Ohno T., Takahashi T., Hirohashi T., Kanno T., Iwaasa H., Kanatani A., and Fukami T. Bioorg. Med. Chem. Lett. 14 (2004) 1761
15. Fermini B., and Fossa A.A. Nat. Rev. Drug Discovery 2 (2003) 439
16. Roden D.M. N. Engl. J. Med. 350 (2004) 1013
17. ™ microplate scintillation counter (Packard, Meriden, CT). Non-specific binding was determined in the presence of an excess amount of cold porcine PYY (1 μM).
18. Butcher, J. W.; Claremon, D. A.; Connolly, T. M.; Dean, D. C.; Karczewski, J.; Koblan, K. S.; Kostura, M. J.; Liverton, N. J.; Melillo, D. G. PCT Int. Appl. WO 2002005860.
19. a database, ver. 11.0 (2008) (Advanced Chemistry Development Inc. http://www.acdlabs.com).
20. Dohta Y., Yamashita T., Horiike S., Nakamura T., and Fukami T. Anal. Chem. 79 (2007) 8312
21. The literature suggests that a decrease in lipophilicity is effective for reducing hERG activity. See:. Jamieson C., Moir E.M., Rankovic Z., and Wishart G. J. Med. Chem. 49 (2006) 5029
22. Fraley M.E., Arrington K.L., Buser C.A., Ciecko P.A., Coll K.E., Fernandes C., Hartman G.D., Hoffman W.F., Lynch J.J., McFall R.C., Rickert K., Singh R., Smith S., Thomas K.A., and Wong B.K. Bioorg. Med. Chem. Lett. 14 (2004) 351
23. ™ microplate scintillation counter (Packard, Meriden, CT). See:. Dautzenberg F.M., Higelin J., Pflieger P., Neldhart W., and Guba W. Neuropharmacology 48 (2005) 1043
24. Kanatani A., Ishihara A., Iwaasa H., Nakamura K., Okamoto O., Hidaka M., Ito J., Fukuroda T., MacNeil D.J., Van der Ploeg L.H.T., Ishii Y., Okabe T., Fukami T., and Ihara M. Biochem. Biophys. Res. Commun. 272 (2000) 169
25. The transcellular transport ratios (B-to-A/A-to-B ratio) for 3d were 1.5 and 6.5 in human and mouse P-gp transfected cells, respectively. In this P-gp transport assay, a compound with a B-to-A/A-to-B ratio above 3 is considered to be a P-gp substrate. See Ref. 22 for experimental details.
26. Yamazaki M., Neway W.E., Ohe T., Chen I., Rowe J.F., Hochman J.H., Chiba M., and Lin J.H. J. Pharmacol. Exp. Ther. 296 (2001) 723
27. Lankas G.R., Cartwright M.E., and Umbenhauer D. Toxicol. Appl. Pharmacol. 143 (1997) 357
28. Umbenhauer D.R., Lankas G.R., Pippert T.R., Wise L.D., Cartwright M.E., Hall S.J., and Beare C.M. Toxicol. Appl. Pharmacol. 146 (1997) 88
29. Male CF-1 Abcb1a (-/-) mice (Charles River, Japan) were used. After 15 h starvation, each mouse was administered vehicle (0.5% methylcellulose solution) or 3d (30 mg/kg) intraperitoneally at a volume of 10 mL/kg. After the administration, mice were given palatable diet (moderately-high fat (MHF) diet, Oriental BioService Kanto, Japan) to accelerate the feeding response. Food consumption was measured 30 min after access to food. Data were expressed as the mean ± SE. n = 7-8 mice/group (ANOVA followed by Dunnett's test).